Is MLPH p.Ala408Ser (c.1222G>T) pathogenic?

MLPH p.Ala408Ser (c.1222G>T) is classified Benign in MLPH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-11-12). AlphaMissense: likely benign (0.0809); Common (popmax 14.3%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about MLPH p.Ala408Ser (c.1222G>T)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

MLPH p.Ala408Ser

Q: How common is MLPH p.Ala408Ser (c.1222G>T) in the general population?

MLPH p.Ala408Ser (c.1222G>T) is common (popmax 14.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1222G>T · rs61737681 · VCV1246554

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 14.3%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -6.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.46	GERP -2.6
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	0.197	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 14.3% African / African-American · 10,721/74,974 alleles

Filtering AF 14.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 14%

Overall 4.71% 75,962/1,613,254 alleles · common exomes 65,007/1,461,004 · genomes 10,955/152,250 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	14.3%	7
Amishnot grpmax-eligible	10.5%	9
South Asian	9.28%	11
East Asian	6.41%	16
Finnishnot grpmax-eligible	6%	17
Middle Eastern	5.8%	17
Admixed American	5.36%	19
Remaining individualsnot grpmax-eligible	5.32%	19
Ashkenazi Jewishnot grpmax-eligible	4%	25
European (non-Finnish)	3.55%	28

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MLPH
Protein: p.Ala408Ser
Coding: c.1222G>T
MANE Select: NM_024101
dbSNP: rs61737681
Type: single nucleotide variant
Location: chr2:237540465 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 408: the 'disordered' region

Full MLPH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MLPH p.Arg35Gln Pathogenic/Likely pathogenic ★★ same type
MLPH p.Arg35Trp Pathogenic/Likely pathogenic ★★ same type
MLPH p.Ala236Thr Uncertain significance ★★ ⚠ same type
MLPH p.Ala520Ser Uncertain significance ★★ ⚠ same type
MLPH p.Arg375Cys Uncertain significance ★★ ⚠ same type
MLPH p.Arg507Trp Uncertain significance ★★ ⚠ same type
MLPH p.Arg518Gly Uncertain significance ★★ ⚠ same type
MLPH p.Asp194Asn Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mlph-p-ala408ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown